Project Summary/Abstract Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The general objective of our research is to understand the cellular and molecular basis of long-term regulation of energy homeostasis in order to identify genes in which mutations cause obesity in humans and to discover new targets for the treatment of obesity. This research proposal focuses on the G-protein coupled Melanocortin-4 Receptor (MC4R), a gene expressed in the central nervous system and implicated in the regulation of food intake. Different mutations in the coding sequence of MC4R cause severe obesity in humans. In this proposal, we will extend our recent novel findings related to the genetic and cellular biology of MC4R. Specifically, we will study the disease consequences of the observation that only one copy of the MC4R gene is active in each neuron expressing this receptor. We will also study the importance of the observation that MC4R localizes to the primary cilia, a cellular organelle that serves as a signaling hub for eukaryotic cells in general and neurons in particular.